Multiple myeloma is a clinically and genetically heterogeneous disease. One half of patients have hyperdiploidy and the other half have one of five recurrent immunoglobulin gene translocations. In both cases these are felt to represent primary genetic events, with the consequence of dysregulation of the expression of a cyclin D gene. Subsequent tumor progression occurs with activating mutations of RAS, secondary translocations of MYC, and inactivating mutations of p53. Recently we have identified a promiscuous array of mutations that activate primarily the non-canonical NFkB pathway. The most common is inactivation of TRAF3 in -13% of MM patients that appears to identify patients with a low response to glucocorticoids, and a high response to proteasbme inhibitors. The tumor acquisition of so many mutations focused on this single pathway highlights its critical importance to the MM cell. We hypothesize that in the majority of patients the pathway is activated as a result of ligand-dependent interaction in the bone marrow microenvironment, and only a fraction (~20%) of patients acquire mutations causing constitutive activation. We propose to dissect out the mechanisms causing activation of the canonical and non-canonical NFkB pathway in MM patients. We hypothesize that both in the presence of ligand-dependent, as well as ligandindependent activation of this pathway, there will be a favorable therapeutic index to its inhibition. We propose to study the functional consequence of specific targeted inhibition using small molecule inhibitors in relevant pre-clinical models. Finally, we propose to introduce into clinical trials targeted NFkB pathway inhibitors showing promise in pre-clinical studies.